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C J Kelly

Publications and source records attributed to C J Kelly.

At least 91 records · Page 5Linked to original sources
PubMed1991

Protein-calorie malnutrition impairs host defense against Candida albicans.

Protein-calorie malnutrition (PCM) impairs immune responsiveness predisposing to Candida albicans sepsis, but mechanisms are unclear. This study examined the effect of PCM on enteric-derived C. albicans intestinal translocation and the ability of in vivo interferon-gamma (IFN-gamma) to upregulate macrophage (MO) candidacidal mechanisms in PCM mice. Control (24% casein) and low protein (2.5%) diets were given for 4 weeks. Mice (n = 160) were fed C. albicans in their drinking water for 3 days and C. albicans translocation (mean colony-forming units (CFU)/g tissue +/- SEM) to the GI tract, liver, spleen, and kidney was assessed at 1 and 5 days following endotoxin challenge of 1, 5, and 10 mg/kg body wt. In a separate study (n = 100 mice), IFN-gamma (1000-10,000 U/day ip) vs saline was given for 3 days prior to harvesting peritoneal macrophages for assay of superoxide anion (O2-), percentage macrophage phagocytosis of C. albicans, and percentage killing of C. albicans. On Day 1, fungal translocation to the intestinal wall and systemic organs in the PCM group was significantly higher. On Day 5, mean CFU were significantly higher in the PCM group, indicating impaired organ clearance. Mean O2-, phagocytosis, and killing were significantly impaired in the PCM group (P less than 0.05), but IFN-gamma improved all functions. PCM significantly depressed host responses to C. albicans. IFN-gamma treatment enhanced candidacidal mechanisms, suggesting a therapeutic role in the malnourished host predisposed to C. albicans sepsis.

Animals↗
PubMed1991

An investigation of the pathophysiology of ischaemic neuropathy.

This study assesses the changes in the microvasculature of peripheral nerves in acute large vessel ischaemic neuropathy. An animal model of large vessel ligation, producing an ischaemic neuropathy was used: the presence and extent of the neuropathy was documented by clinical examination and nerve conduction studies. The nerve microcirculation, the "vasa nervorum" was examined using casting materials, methyl methacrylate and silicone rubber, which were in turn examined by light microscopy and scanning electron microscopy. In all, ten animals were used, all of whom showed clinical evidence of an ischaemic neuropathy 1 week post-ligation. This ischaemic neuropathy was confirmed by nerve conduction studies. Corrosion casts were produced in five of the ten animals. Examination of these casts showed that all five had an area of underfilling of the microcirculation in the region of the proximal tibial nerve with good filling of vessels proximal and distal to this, indicating that in generalised hypoperfusion states such as large vessel ligation, the area of poorest perfusion (and thus maximal damage) is not the distal vascular field, but a probable "watershed zone" between two adjacent nutrient vessels to the nerve.

Animals↗
PubMed1991

Rat alveolar epithelial cells concomitantly express plasminogen activator inhibitor-1 and urokinase.

There is considerable evidence to suggest that intra-alveolar plasminogen activation is instrumental in many aspects of inflammatory lung injury and subsequent tissue repair. Rat alveolar epithelial cells produce large quantities of urokinase-type plasminogen activator (uPA) in vitro, and uPA expression is modulated in association with cellular differentiation and exposure to inflammatory mediators. We now report that these cells also secrete heat-stable PA inhibitory activity having the characteristics of PA inhibitor type 1 (PAI-1). In particular, immunoreactive PAI-1 was demonstrable in conditioned media, cell lysates, and extracellular matrix from epithelial cell cultures. As alveolar epithelial cells differentiated in vitro, secreted PA inhibitor activity increased significantly from 104 +/- PAI U/ml (n = 5, mean +/- SE) on day 2 to 442 +/- 150 on day 7 in parallel with increases in secreted and matrix-associated immunoreactive PAI-1. PAI-1 mRNA expression decreased over this same period suggesting posttranscriptional regulation. The levels of both newly synthesized antigen and PAI-1 mRNA were increased by exposure to lipopolysaccharide and tumor necrosis factor-alpha. Thus, by the coexpression of uPA and PAI-1, the alveolar epithelium may actively regulate the generation of plasmin in both the normal and injured alveolus.

Animals↗
PubMed1991

Effector mechanisms in organ-specific autoimmunity. I. Characterization of a CD8+ T cell line that mediates murine interstitial nephritis.

To further investigate mechanisms of cell-mediated tissue destruction in an organ-specific autoimmune disease, we have established and characterized a nephritogenic CD8+ T cell line. This target antigen-specific effector T cell line, M52, was derived from bulk populations of CD8+ T cells isolated from susceptible animals immunized to produce anti-tubular basement membrane (alpha TBM) disease. Our studies show that M52 retains the phenotypic and functional characteristics of nephritogenic T cells induced in vivo. M52 mediates antigen-specific delayed-type hypersensitivity (DTH) responses to the target antigen 3M-1, it is cytotoxic to 3M-1-expressing renal tubular epithelial cells in vitro, and it adoptively transfers interstitial nephritis to naive syngeneic recipients. Clonal analysis of these nephritogenic CD8+ T cells reveals distinct functional phenotypes within the M52 cell line. We have isolated a cytotoxic CD8+ clone, M52.26, which is not DTH-reactive to 3M-1, and multiple DTH-reactive clones which mediate less efficient cytotoxicity to 3M-1-expressing target cells. Cytofluorographic analysis of four randomly selected clones reveals alpha beta T cell receptor expression. Further characterization of these functionally distinct CD8+ T cell clones will help to define their respective roles in mediating tubular epithelial cell injury and the inflammatory lesion of autoimmune interstitial nephritis.

Amino Acid Sequence↗
PubMed1991

Immunosuppressive mechanisms in protein-calorie malnutrition.

Protein-calorie malnutrition (PCM) induces immunosuppression leading to increased mortality rates. Impaired macrophage respiratory burst activity (superoxide anion [O2-] generation) occurs in PCM, but cellular mechanisms are unclear. The major pathway resulting in O2- production involves inositol lipid-dependent signal transduction. This study examined the effect of mild versus severe PCM on macrophage O2- generating signal transduction pathways specific for responses to Candida albicans. Mice (CFW/Swiss Webster: n = 300) were randomized to either control or low protein diets for 3 or 8 weeks. Peritoneal macrophages were harvested for O2- production, mannose-fucose receptor (MFR) expression, membrane phospholipid analysis, arachidonic acid (AA) content, prostaglandin E2 (PGE2) production, and protein kinase C levels. O2- release was impaired in both mild and severe PCM. MFR expression was also decreased at these time points. Inositol lipid content was significantly lower at the 8-week time point only, although PGE2 and AA were significantly higher in the low protein diet group at 3 weeks. Protein kinase C levels were unchanged by PCM. Thus, mild PCM significantly increases macrophage-PGE2 production secondary to increased AA phospholipid content, with subsequent inhibition of O2- and MFR expression. Severe PCM inhibits macrophage (O2-) through depletion of critical membrane phospholipid components with subsequent impairment in signal transduction.

Animals↗
PubMed1990

Murine interstitial nephritis. IX. Induction of the nephritogenic effector T cell repertoire with an antigen-specific T cell cytokine.

The experiments presented in this report describe the biochemical and functional characteristics of a soluble Th cell factor (ThF) which can induce a nephritogenic effector T cell repertoire producing autoimmune interstitial nephritis. The ThF is Ag-specific, I-A-restricted, and comprises two chains noncovalently linked as a heterodimer. One chain at approximately 78,000 Mr is related to the TCR/Id and expresses a framework determinant (14-30) common to Ag-binding factors, and the other chain at approximately 82,000 Mr is I-A+. Together these chains can replace their parent cell by providing cognate help to precursor effector T lymphocytes in the presence of accessory cells, tubular Ag, and IL-2.

Animals↗
PubMed1990

T cell regulation of autoimmune interstitial nephritis.

Research in organ-specific autoimmunity has been greatly facilitated over the past decade by advances in cellular and molecular immunology. Such studies have greatly expanded our understanding of autoimmune effector mechanisms and the nature of the target antigens recognized by these mediators. Another facet of organ-specific autoimmunity concerns the definition of those factors that determine host susceptibility to disease. This review outlines studies performed in two models of autoimmune interstitial nephritis that focus on issues of susceptibility and tolerance to parenchymal self antigens. In both models, antigen-specific regulatory T cells modulate the effector limb of the nephritogenic immune response and the pattern of interstitial injury. This modulation can be either stimulatory or inhibitory. The dominant regulatory effect is linked to genes in the major histocompatibility locus and is tightly correlated with disease expression. Regulatory T cells which inhibit the nephritogenic immune response can also be cultured in vitro and are highly efficacious as a therapeutic modality. These studies provide both the background and requisite reagents for delineating the mechanism(s) underlying antigen-specific T cell regulation.

Animals↗
PubMed1989

Protective modulation of class II MHC gene expression in tubular epithelium by target antigen-specific antibodies. Cell-surface directed down-regulation of transcription can influence susceptibility to murine tubulointerstitial nephritis.

We have been studying the factors which permit autoimmune injury to the kidney leading to interstitial nephritis. Nonsusceptible mice develop L3T4+ effector T cells which do not recognize their 3M-1 target Ag, nor produce interstitial lesions in the kidney unless proximal tubular class II MHC Ag expression is increased, for example, by rIFN-gamma. Anti-tubular basement membrane/alpha 3M-1-Ab, normally present in such mice after immunization with 3M-1, produce an opposite result by diminishing class II transcription and expression. This unique antibody-ligand interaction on the surface of proximal tubular epithelium secreting 3M-1 serves as a novel protective regulatory response in interstitial parenchyma. The in vitro studies conveyed in this current report suggest that alpha 3M-1-Ab mediate this protective effect by reducing the transcription of mRNA encoding class II gene products. These findings, within the overall complexity of a nephritogenic immune response, demonstrate the important role certain elements may play in maintaining functional nonsusceptibility to autoimmune injury.

Animals↗
PubMed1989

Mandatory premarital testing for human immunodeficiency virus. The Illinois experience.

During the first 6 months of legislatively mandated premarital testing for human immunodeficiency virus in Illinois, 8 of 70,846 applicants for marriage licenses were found to be seropositive, yielding a seroprevalence of 0.011%. The total cost of the testing program for 6 months is estimated at $2.5 million or $312,000 per seropositive individual identified. Half of the reported seropositive individuals reported a history of risk behavior. During the same period, the number of marriage licenses issued in Illinois decreased by 22.5%, while the number of licenses issued to Illinois residents in surrounding states increased significantly. We conclude that mandatory premarital testing is not a cost-effective method for the control of human immunodeficiency virus infection.

Costs and Cost Analysis↗
PubMed1989

T cell recognition of epithelial self.

The presentation of self-antigens to circulating T cells is a critical, precipitating event in the induction of autoimmune injury in parenchymal organs. Epithelia expressing these self-antigens are thought to release such moieties for reprocessing by traditional antigen-presenting cells within the lymphoid system. We now demonstrate, however, that some epithelium possess novel functional mechanisms for presenting their own antigens to a responsive, syngeneic T cell repertoire. The presentation of these self-antigens occurs in the context of MHC class II molecules and depends on CD4 associative-recognition determinants. Our findings strongly suggest that organ epithelium may directly activate cell-mediated events to produce autoimmunity through self-recognition.

Animals↗
PubMed1989

Care of the poor: a story worth telling. A system speaks up and says what it means.

Traditionally, those in Catholic healthcare have considered it bad taste to "toot your own horn" for anything done on behalf of the poor. Such reticence was admirable and reasonable in a stable environment, but a turbulent environment requires more assertiveness. Today, healthcare is a whole new game, with new ground rules. It behooves all players to be more critical of all they do, even when "doing good." The Sisters of Charity Health Care Systems (SCHCS), Inc., Cincinnati, established its Task Force for the Poor to explore and initiate new ways to address the needs of the poor, to find strategies for new forms of service, and to develop mechanisms to evaluate those new services and report the results. But with 22 acute care institutions serving different markets in six states, SCHCS had to establish some uniformity to plan, budget, audit, and report the entire spectrum of its charitable activities. The task force proposed developing uniform measures (definitions) of the charity care provided in traditional inpatient and outpatient settings, as well as that provided through services on behalf of the poor but not captured by standard accounting measures.

Catholicism↗
PubMed1988

The selection of effector T cell phenotype by contrasuppression modulates susceptibility to autoimmune injury.

The genetic susceptibility to murine alpha TBM disease is a dominant trait that maps to H-2K. In previous studies we have shown that the critical difference between susceptible (SJL) and nonsusceptible (B10.S(8R] mice is the phenotype of the tubular Ag-specific effector T cells (TDTH). In SJL mice, these TDTH are Lyt-2+, whereas in B10.S(8R) mice the TDTH are L3T4+. These phenotypic differences have an important functional correlate: Lyt-2+ TDTH are nephritogenic, whereas L3T4+ TDTH are typically not nephritogenic. Both mouse strains have the potential to differentiate both L3T4+ and Lyt-2+ TDTH. The preferential selection of a single TDTH phenotype in each is the result of differential T cell regulation. In the present studies, we have examined the contribution of suppressor and contrasuppressor T cells in the regulation of TDTH phenotype selection. Our studies show that in both SJL and B10.(8R) mice, after exposure to Ag, a suppressor T cell subpopulation functions to inhibit the nephritogenic Lyt-2+ TDTH. In SJL, but not B10.S(8R) mice, this suppression is counterbalanced by Lyt-2+, Vicia Villosa lectin-adherent T cells. Such contrasuppressor function is mediated through a T cell-derived soluble protein (TcsF), which is Ag-binding and recognized by alpha I-JS antisera. This functional TcsF activity maps, as does susceptibility to disease, to H-2K. In the presence of genetically compatible TcsF, the TDTH phenotype in nonsusceptible mice switches to that of susceptible mice. These Lyt-2+ TDTH from nonsusceptible mice are fully capable of inducing tubulointerstitial nephritis following adoptive transfer. Our studies describe a new role for Tcs cells and augment our understanding of their etiopathogenetic role in autoimmunity.

Animals↗
PubMed1988

Characterization of a renal tubular epithelial cell line which secretes the autologous target antigen of autoimmune experimental interstitial nephritis.

Proximal tubular epithelial cells from mice which develop autoimmune interstitial nephritis were found to express the nephritogenic target antigen, 3M-1. Anti-3M-1 mAbs (alpha 3M-1-Ab) were used to positively select for 3M-1-secreting tubular epithelium and, after stabilization in culture, this new cell line (MCT) was examined for the production of several moieties important to either immune interactions or to the development of extracellular matrix. Alkaline phosphatase-staining MCT cells also express epithelial growth factor receptors with a Kd of 0.87 nM and an epithelial growth factor receptor constant (Ro) of 2.1 X 10(4) receptors/cell. MCT culture supernatants contain greater amounts of laminin, and types IV and V procollagens compared to types I and III procollagens, and growing MCT cells on type I collagen matrix causes them to preferentially secrete even more type IV and V procollagen. The 30,000-Mr 3M-1 antigen could be immunoprecipitated from biosynthetically labeled MCT cell supernatants with alpha 3M-1-Ab. An identical-sized moiety was isolated by immunoaffinity chromatography from collagenase-solubilized mouse kidney tubular basement membranes. The 3M-1 antigen can be found on the MCT cell surface by radioimmunoassay, or deposited in a linear array in the extracellular matrix surrounding the MCT cells in culture by immunofluorescence. Mature messenger RNA species for both class I and class II major histocompatibility complex (MHC) molecules were detected by Northern hybridization, and their corresponding cell surface gene products were detected by cytofluorography of MCT cells stained with haplotype-specific antibodies. Both the cell surface 3M-1 and the small amounts of detected class II MHC molecules appear to be biologically functional, as MCT cells can support the proliferation of 3M-1-specific, class II MHC-restricted helper T cells in culture. These findings suggest that MCT cells provide all the necessary biological parameters for interfacing both as the target of a nephritogenic immune response, and as a potential source for new extracellular matrix which develops as a fibrogenic response to interstitial nephritis.

Animals↗
PubMed1988

Elution of kidney-bound antibody by pH-shift does not discriminate between antibodies differing in functional affinity for their ligand.

Antibodies eluted from kidneys by traditional methods of pH shift have been used as reagents in a wide variety of experimental analyses without knowledge of whether their ligand affinity influenced their removal from parenchymal tissue. In the current study we employed two monoclonal antibodies, differing only in their functional affinity (high; K = 2.1 x 10(8)/M and low; K = 6.2 x 10(6)/M) to a common ligand found on the renal basement membrane, to evaluate whether a standard elution technique might selectively facilitate the removal of one antibody over the other. Our findings indicate, however, that the routine methods of elution by pH shift remove both antibodies equally well (41-48%), and without loss of paratypic function. These results provide new evidence that elution by pH shift can produce eluate antibodies which are not biased by preferred affinities.

Animals↗
PubMed1987

Murine interstitial nephritis. VII. Suppression of renal injury after treatment with soluble suppressor factor TsF1.

We prepared soluble suppressor T cell factor (TsF1) from donor spleens harvested from mice primed with tubular antigen-derivatized lymphocytes to analyze both its functional interactions with a larger suppressor T cell network and its influence on the nephritogenic effector T cell response producing interstitial nephritis to a parenchymal antigen. Our findings indicate that TsF1 is antigen-specific, genetically restricted by I-J in its direct mediation of suppression, and capable of inhibiting the development of interstitial lesions. TsF1 also provides an inducing signal for the activation of effector Ts-2 suppressors following presentation by accessory cells. The induction of a Ts-2 effect, however, requires that the factor-presenting cell and the recipient of such cells share homology at I-J, and that the TsF1, the precursor Ts-2 cells, and the recipient of the Ts-2 effect share the same Igh-V allotype. Finally, the results of this current report clearly demonstrate a possible therapeutic role for soluble suppressor factors in the management of interstitial renal disease.

Animals↗